A platelet is anuclear blood cell playing an important role in physiological hemostasis and pathological thrombosis, and is continuously produced from megakaryocytes in a living organism. The platelet originates from pluripotent stem cells like other blood cells. Specifically, the pluripotent stem cell becomes a megakaryocytic progenitor cell, from which megakaryoblasts, promegakaryocytes, and megakaryocytes are formed. During the maturation of a megakaryocyte, premature megakaryocytes only carry out DNA synthesis without involving cell division to become a polyploid. Thereafter, cytoplasm begins to mature to form a platelet separation membrane, and a platelet is released by cytoplasm fragmentation.
In addition, since decrease in the number of platelets due to various hematopoietic dysfunctions in aplastic anemia, myelodysplastic syndrome, or chemotherapy or radiotherapy for malignant tumors and the like causes serious symptoms such as hemorrhagic tendencies, there have been many attempts at developing various technologies for increasing the number of platelets for the purpose of treating such dysfunctions. At present, although platelet transfusion is a powerful means for treating thrombocytopenia, a sufficient amount of platelets cannot be provided, and it is difficult to sufficiently improve thrombocytepenia because of a short life span of transfused platelets and the like. Additionally, platelet transfusions involve problems including viral infection, production of alloantibodies, Graft Versus Host Disease (GVHD), and the like. Thus, there is a demand for the development of a medicament for mitigating hematopoietic suppression caused by various conditions or therapies to thereby promote the recovery of platelet number.
Meanwhile, it has been reported that thrombopoietin (hereinafter referred to as “TPO”), which is a c-Mpl ligand playing an important role in differentiation into megakaryocytes, has been cloned, and that it stimulates differentiation and proliferation of megakaryocytes to promote production of platelets (Kaushansky K. et al., Nature, 369, 568-571, 1994: Non-patent Document 1). Clinical tests on TPO as an agent for increasing the number of platelets have been carried out, and its availability and admissibility in humans have been confirmed. However, because a neutralizing antibody was confirmed in a clinic test of PEG-rHuMGDF, a kind of TPO (163 N-terminal amino acids of native TPO modified with polyethyleneglycol) (Li J. et. al., Blood, 98, 3241-3248, 2001: Non-patent Document 2, and Basser R. L. et. al., Blood, 99, 2599-2602, 2002: Non-patent Document 3), there is a concern about immunogenicity of TPO. And, because TPO is a protein, it is decomposed in the digestive tract, and thus is not practical as an agent for oral administration. For the same reason, it is considered that a low molecular peptide is also not practical as an agent for oral administration. Under these circumstances, the development of a nonpeptide c-Mpl ligand, which has low immunogenicity and can be orally administrated, for the purpose of treatment of thrombocytepenia, is under progress.
As such compounds, benzazepine derivatives are disclosed in Japanese Laid-Open Patent Publication No. Hei 11-152276 (Patent Document 1), acylhydrazone derivatives in WO 99/11262 (Patent Document 2), diazonaphthalene derivatives in WO 00/35446 (Patent Document 3), pyrrolocarbazole derivatives in WO 98/09967 (Patent Document 4), pyrrolophenanthridine derivatives in Japanese Laid-Open Patent Publication No. Hei 10-212289, and pyrrolophthalimide derivatives in Japanese Laid-Open Patent Publication No. 2000-44562.
And, it is described in WO 01/07423 (Patent Document 7) that a compound represented by the following general Formula (VII) has an activity of increasing the number of platelets:

(wherein symbols are as defined in the above publication).
In addition, the above publication discloses a compound wherein X1 is an optionally substituted thiazole, and Y1 comprises —NHCO—. However, Ar1 or Ar2 of the compound of the present invention is not substituted with a substituent group having an A1 group such as a thiazolyl group as in the above publication. Also, the above publication does not disclose concretely in the Examples and the other parts a compound wherein the 5-position of thiazole is directly substituted with a nitrogen atom.
It is also described in WO 01/53267 (Patent Document 8) that a compound represented by the following general Formula (VIII) has an activity of increasing the number of platelets:X1—Y1—Z1—W1  (VIII)
(wherein symbols are as defined in the publication).
The above publication describes a compound wherein X1 is an optionally substituted thiazole, and Y1 comprises —NHCO—. However, Ar1 or Ar2 of the compound of the present invention is not substituted with a substituent group having a W1 group. And, the above publication does not disclose concretely in the Examples and the other parts a compound wherein the 5-position of thiazole is directly substituted with a nitrogen atom.
In addition to the Patent Documents 7 and 8, it is described in Japanese Patent Publication No. 3199451 (Patent Document 9) that a 2-acylaminothiazole compound has the effects of a cholecystokinin and gastrin receptor agonist, and it is described in Chemical and Pharmaceutical Bulletin, 25, 9, 2292-2299, 1977 (Non-patent Document 4) that a 2-acylaminothiazole compound has anti-inflammatory effects. However, there is no description about activity for increasing the number of platelets.
Under these circumstances, there is a demand for the development of a nonpeptide c-Mpl ligand that has low immunogenicity and can be orally administrated, for the purpose of treatment of thrombocytepenia.    [Patent Document 1] Japanese Laid-Open Patent Publication No. Hei 11-152276    [Patent Document 2] WO 99/11262 pamphlet    [Patent Document 3] WO 00/35446 pamphlet    [Patent Document 4] WO 98/09967 pamphlet    [Patent Document 5] Japanese Laid-Open Patent Publication No. Hei 10-212289    [Patent Document 6] Japanese Laid-Open Patent Publication No. 2000-44562    [Patent Document 7] WO 01/07423 pamphlet    [Patent Document 8] WO 01/53267 pamphlet    [Patent Document 9] Japanese Patent Publication No. 3199451    [Non-patent Document 1] Nature, 1994, 369, p. 568-571    [Non-patent Document 2] Blood, 2001, Vol. 98, p. 3241-3248    [Non-patent Document 3] Blood, 2002, Vol. 99, p. 2599-2602    [Non-patent Document 4] Chemical and Pharmaceutical Bulletin, 1977, Vol. 25, 9, p. 2292-2299